Development of TCR Antagonists to MBP-Reactive T-Cells

Multiple sclerosis (MS) is a chronic immune mediated disease characterized by recurrent attacksof neurologic dysfunction due to damage to the central nervous system. An animal model of MS,experimental allergic encephalomyelitis (EAE), also shows similar neurologic damage caused by T cellswhich recognize a portion (amino acids 89-101) of myelin basic protein (MBP), a major constituent ofthe myelin sheath surrounding nerve cells. Recently, a peptide analog of MBP corresponding to the region89-101 has been found to interfere with antigen recognition by T cells involved in the pathogenicity ofthis disease. Moreover, this peptide was able to inhibit the development of EAE when co-administeredwith MBP. We will conduct additional analoging efforts to identify the minimal peptide necessary toinhibit these self-reactive T cells in a variety of in vitro and in vivo assays. Further modifications areplanned using D-amino acid substitutions to prolong the half-life and enhance the therapeutic benefit ofthe drug. This approach may help to identify compounds which are orally active, lipophilic and capableof passing the blood-brain barrier, and may aid in our management of MS.